Naslov
In vitro and in vivo effects of prolonged benzodiazepine exposure: comparison between diazepam and zolpidem

Autori
Švob Štrac Dubravka ; Vlainić, Josipa ; Jazvinšćak Jembrek, Maja ; Peričić, Danka

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, neobjavljeni rad, znanstveni

Skup
FENS/IBRO European neuroscience school "Drugs and the Brain: an Update in Psycho-pharmacology from Experimental to Clinic"

Mjesto i datum
Braga, Portugal, 26.04.2012. - 27.04.2012

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
recombinant GABA-A receptors; HEK 293 cells; mice; prolonged exposure; withdrawal; diazepam; zolpidem

Sažetak
Prolonged exposure to benzodiazepines leads to adaptive changes in GABA-A receptors. To explore underlying mechanisms we studied the effects of prolonged benzodiazepine treatment on the recombinant α1β2γ2S GABA-A receptors stably expressed in HEK 293 cells. Long-term exposure of these cells to zolpidem (10 μM), as well as to a higher (50 μM), but not to a lower (1 μM), concentration of diazepam, increased the number of binding sites for GABA, benzodiazepines and convulsants, suggesting the enhancement the overall GABA-A receptor number. Results demonstrating up-regulation of the α1 subunit mRNA, and β2 and γ2 subunit proteins following prolonged exposure to these drugs, suggested increased de novo synthesis of receptor subunits at transcriptional and translational level. Prolonged diazepam and zolpidem administration produced a decrease in the allosteric coupling between benzodiazepine and GABA binding sites. If these functional uncoupling is related to the development of tolerance and dependence to the effects of benzodiazepines, our data might suggest that these phenomena will develop following both long-term treatment with diazepam and zolpidem. Moreover, 24 h after the discontinuation of long- term diazepam and zolpidem treatment, the number of GABA-A receptor binding sites returned to control levels. Zolpidem withdrawal also normalized the levels of γ2 subunit proteins. However, although withdrawal from zolpidem normalized functional interactions between GABA and benzodiazepine binding sites, allosteric uncoupling was still present 24 h after the termination of diazepam treatment. Hence, although prolonged zolpidem treatment triggered the adaptive changes in GABA-A receptors (i.e. up- regulation and allosteric uncoupling), which are not substantially different from those obtained after prolonged exposure of cells to high concentrations of classical benzodiazepines, the functional recovery of GABA-A receptors was achieved sooner after zolpidem than after diazepam withdrawal. While early studies suggested that zolpidem does not produce tolerance and physical dependence, our results also demonstrated that mice treated repeatedly with zolpidem for 10 days develop tolerance to its sedative and anticonvulsant effects. Moreover, our experiments also showed that zolpidem might be a better convulsant than previously thought and that after repeated treatment ; zolpidem and diazepam are approximately equipotent anticonvulsants, at least against convulsions induced by i.v. infusion of pentylenetetrazole.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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